Diabetes affects over 16 million Americans. The World Health Organization indicates that diabetes afflicts 120 million people worldwide, and estimates that this number will increase to 300 million by the year 2025. Diabetics are faced with numerous complications including kidney failure, non-traumatic amputations, an increase in the incidence of heart attack or stroke, nerve damage, and loss of vision. Diabetic retinopathy is a form of visual impairment suffered by diabetics.
In particular, diabetic retinopathy is responsible for 13.1% and 18.2% newly reported cases of blindness for men and women, respectively. Kohner E. M., et al. Diabetic Retinopathy Metabolism, 25:1985-1102 (1975). The prevalence of blind diabetics in the population is about 100 people per million. Id.
Less than optimal methods of treatment for diabetic retinopathy exist. For example, laser treatment may be used to slow the progression of edema, but it cannot be used to reverse the symptoms of diabetes. Accordingly, a need exists to develop effective methods of treatment to reduce or impede vision loss and/or diabetic retinopathy.
The present invention relates to methods for inhibiting the binding of a leukocyte to an endothelial cell or another leukocyte in the retinal vasculature. The present invention pertains to methods of treating (e.g., reducing or preventing) retinal injury in a mammal (e.g., human, individual, patient) wherein the injury involves retinal edema or retinal ischemia, comprising administering a compound that inhibits the binding of a leukocyte to endothelium or to another leukocyte wherein a reduction in edema or ischemia (e.g., non-perfusion) occurs. The compound comprises an integrin antagonist (e.g., lymphocyte function associated molecule-1 (LFA-1), Mac-1 or p150,95), a selectin (e.g., P-selectin, E-selectin and L-selectin) antagonist, an adhesion molecule antagonist (e.g., Intercellular Adhesion Molecule (ICAM)- 1, ICAM-2, ICAM-3, Platelet Endothelial Adhesion Molecule (PCAM), Vascular Cell Adhesion Molecule (VCAM)), or a leukocyte adhesion-inducing cytokine or growth factor antagonist (e.g., Tumor Neucrosis Factor-xcex1 (TNF-xcex1), lnterleukin-1 xcex2(IL-1 xcex2), Monocyte Chemotatic Protein-1 (MCP-1) and a Vascular Endothelial Growth Factor (VEGF)). The integrin antagonist can be an integrin subunit (e.g., CD18 or a CD11b) antagonist. The antagonist can be administered with or without a carrier (e.g., pharmaceutically acceptable carrier).
In particular, the invention pertains to methods of treating or preventing retinal injury in a mammal comprising administering to the mammal an adhesion molecule antagonist and/or an integrin antagonist, wherein the adhesion molecule antagonist and/or the integrin antagonist inhibits leukocyte interaction, thereby reducing or preventing retinal injury. The antagonist can be administered in a carrier (e.g., a pharmaceutically acceptable carrier). The antagonist for adhesion molecule can be a VCAM, PCAM, ICAM-2 or ICAM-3 antagonist or, preferably, an ICAM-1 antagonist. In particular, the antagonist can be an antibody or an antibody fragment which is specific for ICAM-1, an antisense molecule that hybridizes to the nucleic acid sequence which encodes ICAM-1, or a peptide mimetics molecule, a ribozyme, an aptamer, or a small molecule antagonist that inhibits ICAM-1. The integrin antagonist can be a LFA-1 antagonist , Mac-1 antagonist or p150,95 antagonist. The integrin antagonist also comprises an integrin subunit antagonist (e.g.,a CD18 antagonist and/or a CD11b antagonist). The antagonist can be an antibody or antibody fragment specific for CD18 and/or CD11b, an antisense molecule that hybridizes to the nucleic acid sequence that encodes CD18 and/or CD11b, or a peptide mimetic molecule, a ribozyme, an aptamer or a small molecule antagonist that inhibits CD18 or CD11b.
Another aspect of the invention includes a method for preventing or treating an individual having retinal injury (e.g., injury caused by diabetic retinopathy), wherein the injury is associated with retinal edema and/or retinal ischemia, comprising administering to the individual a compound that inhibits Mac-1 or a pathway thereof. The compound inhibits ICAM-1, CD18, CD11b, and/or VEGF, and causes a decrease of ischemia and/or edema (e.g., between about 10% and about 90%). Leukocyte interaction can also be reduced. The compound can be an antibody, an antibody fragment, a peptide mimetic molecule, an antisense molecule, a ribozyme, an aptamer and/or a small molecule antagonist. Examples for such a compound are ICAM-1, CD18, CD11b, and/or VEGF.
The invention also pertains to a method of treating an individual having retinopathy or at risk for retinopathy (e.g., diabetic retinopathy) comprising administering an antagonist (e.g., ICAM-1, CD18, CD11b and/or VEGF), as described herein. The antagonist can optionally be administered in a suitable carrier (e.g., pharmaceutically acceptable carrier). Administration of this antagonist results in a decrease in retinal ischemia and/or retinal edema. Preferably, a decrease in ischemia and/or edema occurs by at least about 10%, and more preferably, by about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% (e.g., between 10% and 95%). Accordingly, the present invention also relates to methods for treating or preventing retinal edema and/or retinal ischemia comprising administering an ICAM antagonist (e.g., ICAM-1), a CD18 antagonist, a CD11b antagonist and/or a VEGF antagonist, wherein a decrease in the edema and/or ischemia occurs.
The present invention also relates to methods of treating diabetic retinopathy by administering an ICAM-1, CD18, CD11b and/or VEGF antagonist and at least one additional antagonist that inhibits the binding of a leukocyte to an endothelial cell or to another leukocyte. The additional antagonist can be an integrin antagonist (e.g., an integrin subunit antagonist such as CD18 and/or CD11b), a selectin antagonist, a leukocyte adhesion-inducing or growth factor antagonist, or adhesion molecule antagonist. The additional antagonist can be, for example, another ICAM antagonist (e.g., an antagonist that is specific for a different portion or epitope of the ICAM-1 molecule), a PCAM antagonist or a VCAM antagonist. The types of integrin antagonists, selectin antagonists, and leukocyte adhesion-inducing or growth factor antagonists are described herein.
The invention also encompasses a method of inhibiting leukocyte interaction, comprising contacting a leukocyte, an endothelial cell or a leukocyte adhesion-inducing cytokine, with a compound or antagonist, as defined herein. The compound can be an integrin antagonist (e.g., an integrin sub-unit antagonist such as CD18 and/or CD11b), a selectin antagonist, an adhesion molecule antagonist or a leukocyte adhesion-inducing cytokine or growth factor antagonist. In particular, the invention relates to a method of inhibiting leukocyte interaction, comprising contacting an endothelial cell with an adhesion molecule antagonist (e.g., ICAM-l specific antagonist), an integrin subunit antagonist (e.g., CD18 and/or CD11b specific antagonist), or a leukocyte adhesion-inducing cytokine antagonist or growth factor antagonist (e.g., TNF-1xcex1, IL-1xcex2, MCP-1 and VEGF antagonist).
The invention also pertains to a method of preventing or reducing retinal leukostasis an a mammal comprising administering to the mammal an effective amount of an ICAM, CD18, CD11b and/or VEGF antagonist. The types of antagonist is described herein. The method results in retinal leukostasis reduction by between about 10% and 90o%.
Another aspect of the invention is a method of decreasing retinal leukocyte adhesion in a mammal, comprising administering to the mammal an effective amount of an antagonist that is specific for CD11b, CD18 or a combination thereof. The retinal leukocyte adhesion is decreased between about 10% and 90%.
Yet another aspect of the invention is a method of treating or preventing neovascularization in a mammal, comprising administering to the mammal a CD18 antagonist and an ICAM-1 antagonist, or a CD18 antagonist. The types of antagonists are described herein. The method is applicable to diseases or conditions associated with neovascularization including, but not limited to, age-related macular degeneration, choroidal neovascularization, sickle cell retinopathy, retina vein occlusion, diabetic retinopathy, a condition associated with limbal injury, a condition associated with increased neovascularization, traumatic alkali injury, Stevens Johnson syndrome and ocular cicatricial pemphagoid. The neovascularization can be reduced in the cornea, the retina or the choroid.
Advantages of the present invention include effective treatment for retinopathy, retinal edema, retinal ischemia, neovascularization and other associated disease. Treatment of these diseases and/or conditions have been ineffective until the discovery of the present invention. For the first time, the present invention provides useful methods of treatment which target molecules that are involved in these diseases.